We have sought to understand the mechanisms by which murine leukemia viruses (MuLV) induce tumors by identifying: 1) preleukemic changes in the lymphocyte compartment of MuLV-infected mice using antibodies to cell surface antigens and flow cytometry; and 2) specific defects in lymphocyte ontogeny and function that confer resistance to leukemogenesis. We find that the preleukemic period for Moloney-MuLV-infected mice has three distinct phases: 1) cells with an altered expression of Thy 1 antigen appear in the thymus; 2) the number of lymphohemopoietic precursors in the spleen increases significantly; 3) the turnover of lymphohemopoietic precursors increases significantly. These preleukemic changes are delayed in CBA/N mice, which are resistant to leukemogenesis. Resistance is associated with at least two autosomal genes, one of which controls dualtropic virus replication. An X-linked resistance gene can also be demonstrated in crosses to susceptibel strains.